THE SYNTHESEES OF 513%} TEEEY'UXRY AMENE DERIVA'HVEES OF MSXED l-H‘HEEW’L.‘ ALKYL SULFIDES Thesis for the Dag-:86: a! M. S, Mia-{EGAN STATE CGLLECE M. <3 2:: n H ii K. 5 'z :1 1 (j? :5} This is to certify that the thesis entitled The Synthesis of Some Tertiary Amines Derived from Mixed Phenyl Alkyl Sulfides presented by Moon Hwi Kim has been accepted towards fulfillment of the requirements for Master's degree in Chemistry pm W Major professor Date March 19, 1951 0-169 In. ' a?‘ . 75.3. in") .1\- aI. . :IIIolII .‘sl‘m’ #3:”; ‘ 1917' . p Iffiiflf’ " ' 1:“ ”1'3; ' fly. jg: ' g "If" J.” ’2’: 3W! , w 77 '~ W1 WM ”51.: 4:39" 1"!» ‘ M-‘j' .1 m’ '7'" Minx?“ ‘ 5‘9 'O'? 'f'( ,J.’ "IuI.- ' (:53 4‘ .L'fzoIIf‘; ., 31:. :rI‘IIIpI' 91(ng fTIII'If, 1’" h 1"?“ Walt- ' ‘Cé’l'. gawk” It"? :fIJ la." n I c ,I 2‘ . 't 13). a VI-un-~I'ylc’r*”"’ 35 p.45 ‘0! w: . r,» . s ,4 ”3.): ' .3,- - My», “Ski-m?.‘.'.“r"';-=f-..;«"Af ‘9’" ' , . . «." ~ I .L’SH . . "JIM. ‘L 9 .“W‘. \.. 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M THE SYNTHESES OF SOME TERTIARY.AMINE DERIVATIVES OF MIXED PHENYL ALKYL SULFIDES BY Moon Hwi Kim A THESIS Submitted to the School of Graduate Studies of Nfichigan State College of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1951 CHEMLSTRY 0in r- :77" .- \J 4 \J 'g "rifl‘l ACKNOWLEDGMENT The author wishes to express his appreciation for the aid and guidance given by Doctor Robert D. Schuetz whose suggestions made possible the completion of this work. *t***#***# ******t* ****** **** *4! n: TABLE OF CONTENTS Page II‘TTRODUCTI()1JOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO.00...... 1 HISTOFICALOOOOOOOOOOOOOOOOOOOOOOOOOO00.00.000.000.OOOOOOOOOOOOOOCO 3 DISCTVTSSIONOOO0.00.0000...OOOOOOOOOCOOOOOOOO.OOOOOOOOOOOOOOCOCOOOOC 10 EXPERIMENTAL Preparation of oD-Hydroxyalkyl Phenyl Sulfides............... 23 Preparation of d>-Chloroalky1 Phenyl Sulfides................ 28 Preparation of Tertiary Amine Derivatives of Mixed Phenyl- .A1kyl Sulfides.......................................... 33 Preparation of Polymethylene Chlorohydrins................... 46 Preparation of Derivatives of cb-Hydroxyalkyl Phenyl Sulfides 4B ATEALXISISOOOOOOOOOOOOCOOOOOOOOIIOOOOOOOOOOOOOOOOOOOOOOOOO00....0... 49 Srnx'quRXrOOCOOO0.00....OOOOOOOOOOOOOCOOO00.0.0000...00......0.00.... 51 BIBLIOGIQAPHYOOOOOOOOOO.0.00.0.0000...O.0......OOOIOOOOOOOOOOOOO... 52 VITAOOOOOOOOOOOOOOOCOOOOOOOOOOOOO0.0.0.0000...OOOOOOCOOOOOOOOOOOOO 54 TABLE I. II. III. IV. VI. VII. VIII. LIST OF TABLES Physical Constants Obtained for the w-Hydroxyalkyl Phenyl sulfideSOOIOOOOOOOOOO..00OOOOOOOOOOOOIOOOO... 3,5-Dinit robenzoates of uD-Hyd roxyalkyl Phenyl Sulfid es.. P-Nit rob enz oat es of u) ~Hydroxyalky1 Phenyl Sulfides . . . . . . . Physical Constants Obtained for the a.) -Chloroa1kyl Phenyl SUlfideSooooo0000000000000.0000000000000000000000.00 Physical Constants Obtained for the Tertiary Amine Derivatives of Mixed PhenylAlkyl Sulfides........... Reaction Conditions and Yields Obtained for the w-Hydroxyalkyl Phenyl SUlfideSoooooooooocoooooooooo Reaction Conditions and Yields Obtained for the LD’Chloroalkyl Phanyl SUlfideSooeo0000000000....so.o Reaction Conditions and Yields Obtained for the Tertiary Amine Derivatives of Mixed Phenyl Alkyl Sulfide HzdeOChlorideSCCCOCCOO0.0....COOCUOQOCCOOOOCOOOOOOOC PAGE 12 13 14 15 19 27 32 45 INT RO DUCT I ON An extensive amount of work has been done on the elucidation of the structural relationship of organic compounds to their physiologi- cal and pharmacological properties during the first half of this century. A compound which has the following features in its structure, / A-M-( c )n-N\ where A represents an aryl group, and where M is a heteroatom, has been a keen object of these investigations since therhistorical syn- theses of "Novocaine" by Einhorn.1 Novocaine, an important local anaesthetic of more advantageous physiological action than that of the natural anesthetic "Cocaine", was the famous ancestor of compounds of similar structure. Since the beginning of these investigations an in~ tensive effort has been directed toward the discovery of the types of chemical structures which are responsible for given physiological activities. As a result of this common goal of many investigators, an impor— tant prediction was made by Pyman,2 who generalized the relationship for compounds of the above general structure with respect to their physiological actions. Later L3fgren3 proposed the detailed structural requirements of a compound which would possess local anesthetic properties. Because of the similarity in the chemical structure of sulfides and of others, and because of the usefulness of the latter when they also contain a tertiary amine group, the investigation reported in -1... this thesis was undertaken for the purpose of synthesizing a similar group of mixed tertiary amino phenylalkyl sulfides. These are repre- sented by the general formula: R / -s- ( CH2 )n-N\ A second aim of the present investigation can be ascribed to a study of the effect of the length and branching of the alkyl chain on the physiological activities of these compounds. Thus a systematic attempt was made to vary from two to six carbon atoms the length of the alkyl chain which is attached between the arylthio radical and a few different types of secondary amino groups. In other words, the arylthio radical was kept a constant part of the molecule and the chain length as well as the and secondary amine groups were variables. From the results Obtained in such an investigation, one should be able to draw some comparison between the ether and sulfide analogs with respect to their chemical and physiological properties. Further, one might expect that the slight differences between the sulfides and ethers in.their chemical properties may possibly manifest themselves in important differences in their physiological behaviors. However, it is clear that only the clinical tests, which have not yet been con- ducted, can establish the true value of their physiological usefulness. -2- HISTORICAL Very little work has been reported on the investigation of the physiological and pharmacological effects produced by tertiary amine derivatives of mixed phenyl alkyl sulfides, although a great deal more work has been done regarding the same effects of their ether analogs. Considering the fact that many of these others have been found to be useful for their local anesthetic, antihistaminic, sympathomimetiC, and antimalarial properties, an expectation of usefulness for the sul- fide analogs seemed reasonable because of the close similarity in the structures of the ethers and sulfides. In accordance with the anesthesio- phoric principle relating to the structural constituents among the vast majority of local anesthetics, as proposed by Lb‘Tgren,3 the tertiary amines of mixed phenylalkyl sulfides of the general structure, C6H5S-(CH2)n-N(R)2 could also be classified under the category of Lofgren's general formula for local anesthetics. He suggested that the intermediate chain should consist of a hydrocarbon residue joined to the aromatic structure through either an ester or an amide linkage, which served to increase the physiological activity. The ester or amide linkage might also be replaced by the amine nitrogen, the ketonic carbonyl, or the ether oxygen. The replacement of the ether oxygen by a sulfur atom would be expected to give rise to properties very similar to those possessed by the ethers. One of the very few cases of an investigation of the physiological actions of tertiary amine derivatives of mixed phenyl alkyl sulfides was carried out by Buchél and Tchonbar.4 Their work -3- reported a comparison of p-diethylaminoethyl phenyl sulfide (I) and (3 -diethylaminoethyl o-tolyl sulfide (II) with (3 -diethylaminoethyl phenyl ether (III) and p-diethylaminoethyl o-tolyl ether (IV). (I) C6H58-CH2CH2-N(CZH5)2 (II) O-CH306H4S-CHZCH2-N(C2H5)2 '(III) CGH5O-CH2CH2°N(CZH5)2 (IV) O-CH3C6H4O-CHZCH2°N(CZH5)2 They reported all of the above compounds were hypotensive, adrenolytic, and slightly antihistaminic, but that none showed any local anesthetic action. They also found that the sulfur compounds were slightly less potent than the oxygen compounds in the administration of the lethal intravenous dose in mice. 5 In other investigations carried out by Kohler, it was reported that Q-ethylaminoethyl phenyl sulfide (V) and Q-ethylaminoethyl o-tolyl sulfide (VI) had no protective action against the acute pul- monary edema produced by a one-milligram dosage of adrenalin hydro- chloride in the intravenous injection of a three-kilogram rabbit. However, Q-dimethylaminoethyl phenyl ether (VII) and bis (9-0- toloxyethyl)methylamine (VIII) were found to be quite effective. ,H r T,H CH20N\ (II) CH3C6H4S°CH2CH2-h\ CZH5 C2H5 H 1 (VII) C6H50°CH2CH2-N(CH3)2 (VIII) (CH306H40~CH20h2)2-mcn3 (v) C HES-CH 6 2 However, in none of the limited investigations reported in the litera- ture were sufficient compounds containing sulfur prepared to allow a complete physiological study to be made. This work deals with the preparation of some tertiary amine de- rivatives of mixed phenyl alkyl sulfides, and is confined to their chemistry and does not include any of the physiological studies, which will be reported elsewhere. The historical review of the possible methods available for the synthesis of tertiary amine derivatives of mixed phenyl alkyl sulfides as well as of the intermediates us ed in their preparation, u-hydroxy- alkyl phenyl sulfides and d-chloroalkyl phenyl sulfides, will be dis- cussed in order to indicate why the methods employed in the present investigation were selected. The reactions between sodium phenoxide and ethylenedichloride or l,3-dibromopropane were reported by Marvel6 to yield 55-56%, and 84-85% of the corresponding a-chloroalkyl phenyl ethers respectively, but there was no assurance that this reaction can be applied to thio- phenolate and the same dihalides. The use of (g-chloroethyl-p-toluene- sulfonate as a chloroalkylating agent for sodium phenoxide was initially 7 employed by Clemo and Perkin and gave a better yield of e-chloro- ethyl phenyl other than in the previous method.* CH306H4-SOZC1 4- ClCHzCHZOH-———r CH3C6H4°SOZOCH2CH2C1 + HCl 0 ’ NaOH . 7 CGHSOH + CH306H4 SOZOCHzCthl___;CSH5O CHzCthl + CH3C6H4°SOSNa Another method was us ed by Steinkopr to prepare p-chloroethyl phenyl ether in a 76% yield. This consisted of passing gaseous I"An unpublished investigation by Dr. R. D. Schuetz on the reaction between sodium‘thiophenolate and 9.chloroethy1-p- toluenesulfonate gave a fair yield of at ,@ -dithiophenyl- ethane, besides a rather poor yield of p-chloroethyl phenyl sulfide. -5- hydrogmlchloride into a mixture of phenol, sodhflnhydroxide and ethylene- chlorohydrin in alcoholic solution heated on a steam.bath. HCl OH . NaOH . Cl(CH2)ZOH———-’ C6H50°CH2CHZC1 + NaCl CSH Alcohol 5 Although no extensive investigation has been carried out, olefins have been utilized to prepare wr-chloroalkyl phenyl sulfides from.sul- fenylchloride. Lecher and Stacklin9 passed ethylene into a carbon- tetrachloride solution of phenylsulfenyl chloride under anhydrous conditions and obtained p-chloroethyl phenyl sulfide in a good yield. C6H5301 . CH2 = CH2 ———rCeH58-CHZCH2C1 @ -hydroxyethyl phenyl sulfide was also obtained10 by condensing ethylene oxide with thiophenol in the presence of active charcoal. - T , C v \/ 0 cs 11 Similar reactions were reported for epoxides and phenol in the presence of alcoholic sodimrhydroxide, using a sealed-tube technique, NaOH 06H50H . R-CH-CHz ___, 06H50°CHZCHOH \ / Alcohol I O R but there was no assurance of its applicability using thiophenol. Fuson and Koehneke12 prepared e-hydroxypropyl phenyl sulfide by the reaction between sodhmlthiophenolate and chloroacetone, giving rise to thiophenylacetone which was then reduced by the Meerwein- Ponndorf13 method. 0153 Al(O(CH5)2CH)3 n C6H53Na + ClCrIZS°Chs———-> CGHSS-CHzfiCHs fit C6HSS-CHZCHOH O O They also prepared e-hydroxyisopropyl phenyl sulfide by the sulfur- catalyzed reaction between thiophenol and allyl alcohol. This latter S C6H58H + CH2=CHCHZOH ———> CGHSS-CHCHZOH CH3 with compound rearranged, when treated/thionyl chloride or hydrogenchloride to replace the hydroxyl group by chlorine, to give 9 -chloropropyl phenyl sulfide instead of the expected @ -chloroisopropy1 phenyl sulfide. SOCl2 C6H5S-CHCH20H ~:- CGHSS-CHZCHCl l or HCl CH3 CH 3 Ranshawl4 and co-workers reported that a -dialkylaminomethyl alkyl sulfides my be obtained in good yields by the reaction of mercaptans and secondary amines with formaldehyde, but an extension of this re- action to thiophenol has not been reported. RSH + HCHO + HNRZ RSCHZNRZ 4- H20 An interesting synthesis of @—diethylaminoethyl 2,4-dinitrophenyl sulfide and of W—diethylaminopropyl 2,4-dinitrophenyl sulfide was carried out by Gilmn15 and co-workers in the reactions between (3 -diethylaminoethyl and J-diethylaminopropyl mercaptans with 2,4-di- nitrochlorobenzene. The (3 -and a’ -diethylaminomercaptans were prepared -7- in two different ways. The p -diethylaminoethylmercaptan has been 16 and from prepared from ethylene sulfide and lithiumdiethylamide, the interaction of (3 -diethy1aminoethyl chloride with sodium hydrosul- fide. The later reaction also yields bis(@-diethylaminoethyl) sulfide. (02H5)2NoCHZCHZSH + 0106H3(N02)2 ——_., (CZH5)2N-CHZCHZ-SCSH3(N02)2 (C2H5)2N-CHZCH2CHZSH + 0106H3(N02)2——. (02H5)2N-CHZCH2CH2oSCGH3(N02)2 CHE-CH2 HCl (02H5)3NLi+ \s/ —_.(02H5)2N-CH20H28L1__..(02H5)2N-CHZCHZSH 487 (02H5)2NCHZCH c1 + NaSH -——+ (C2H5)N°CH2CHZSH + (EtzN-CHZCHZ)ZS 2 The If -diethylarninopropyl'mercaptan was prepared in a 55% yield by the reaction of I -diethylaminopropyl chloride with sodium hydrosulfide, using essentially the same procedure as was us ed for the preparation of the lower homolog. It also gave I -diethylaminopropyl 2,4-dinitro- phenyl sulfide by reaction with 2,4-dinitrochlorobenzene as shown in the above equations. The first attempt to prepare e—hydroxyethyl phenyl sulfide was made by Bennet and Berryl7 by adding ethyleneechlorohydrin to a sodium thiophenolate solution. However, they did not succeed in isolating the pure product and reported its transformation into an unsaturated compound on distillation. However, this unstability to heat was not confirmed by Kirner.18 Steinkopr and his co-workers, as previously named, prepared {3-hydroxyethyl phenyl sulfide in a similar manner, -8- but made no attempt to isolate it. The method employed in the present 'work was analogous to that suggested by Powell19 for the preparation of the oxygen analogs and followed the procedure of Kirner18 which was based essentially upon Powell's method. Kirner18 prepared two :0 -hydroxya1kyl phenyl sulfides, namely (3 -hydroxyethyl and \’ -hydroxy- propyl phenyl sulfides. This method gave a smooth reaction with sodhnnthiophenolate and the corresponding chlorohydrins giving good yields of 80-90% of the theoretical in a one hour period at reflux temperatures. NaOH C6H5SH .- Cl(CH2)nOH———-> 06H58-(0H2)nOH Preparation of the first member of the homologous series of .9 -chloroa1kyl phenyl sulfides was first carried out by Steinkopf and his co-workers8 in their synthesis of Q-chloroethyl phenyl sulfide by passing hydrogenchloride into the crude Q -hydroxyethy1 phenyl sulfide to obtain a fair yield of the corresponding chloride. Bonnet and Berry17 obtained both the Q-chloroethyl and ‘u-chloropropyl compounds by the application of the Darzens'zO reaction.to the corresponding hydroxy compounds. The amination of the omega-halogen atom has been reported in the case of @ -bromoethyl Q-naphthyl ether to occur in alcoholic ammonia in a closed system at 100° C. by Koelle.21 Clemo and Perkin7 obtained a better yield of dimethylaminoethyl naphthyl ether using a sealed tube technique and a sixteen-hour period of reaction at 120-140° C. Exten- sion of this reaction to the cb-chloroalkyl phenyl sulfides seemed possible. -9- DISCUSSION After a careful consideration of the various methods which have been used for the preparation of a few of the simpler aJ-hydroxy and 0) -chloroa1kyl phenyl sulfides, as well as those us ed in the synthesis of the tertiaryamine derivatives of mixed naphthyl alkyl ethers, the following procedure was decided upon for use in the present investiga- tions: NaOH CGHSSH + Cl(CH2)nOH ——-—-+-06H58-(0H2)n0H 4 NaCl 4- H20 CSH5S°(CH2)nOH 4- soc12 .———» 06H53°(CH2)nCI + so2 . HCQI 033 E3 C6H5S-(CH2)n01 + 122ml C6H53- ( CH2 )n-NR2 The a) —hydroxyalkyl phenyl sulfides with two to six carbon atoms in the alkyl chain, including one with a branched alkyl chain of three carbon atoms, were prepared by the interaction of thiophenol with the corresponding polymethylenechlorohydrins in aqueous sodium hydroxide, following the procedure developed by Kirnergl8 The reactions were car- ried out smoothly using all reagents in stochiometric quantities and were completed in a period of two-thirds of an hour to an hour and a half at a temperature of 80 to 100° C. In general yields of 80-90% were obtained. The w-hydroxyalkyl phenyl sulfide with a branched chain was prepared from propylene chlorohydrin. The distillation of the m-hydroxy compounds generally required high temperature and high vacuum. For the Q-hydroxyhexyl phenyl sulfide, a waxy solid at room temperature, a short fractionating column with a resistance heater on the side arm was necessary. The properties of the a)-hydroxyalkyl phenyl sulfides which are new are summarized in Table I. The a)-hydroxyalkyl phenyl sulfides were further characterized by preparation of their 3,5-dinitrobenzoates and P-nitrobenzoates. The properties of those derivatives which have not been previously re- ported have been listed in Tables II and III. The e -chloroalkyl phenyl sulfides were obtained from the corres- ponding co-hydroxyalkyl phenyl sulfides by means of the Darzens20 reaction using pyridine as the solvent. Yields of approximately 50 to 90 percent were obtained by treating the cd-hydroxyalkyl phenyl sulfides with a 25% excess of thionyl chloride under carefully controlled con- ditions in order to prevent a sudden rise of the reaction temperature during the addition of the thionyl chloride. This was done by using a cold water bath around the reaction flask. The temperature used to complete the reactions after the addition of the thionyl chloride ranged from.50 to 90° C. At higher temperatures considerable tarring was apt to occur. The end of the reaction was determined by observing the formation of the pyridine hydrochloride in an amount approximately equivalent to the alcohol used. Generally the end of the reaction was reached in about one to one and a half hours in which time the color of the reaction mixture became light brown. The properties of the eb-chloroalkyl phenyl sulfides which have been prepared for the first time are listed in Table IV. .eopnomoa a3 moon-roam soon, obs: heap poo, Jone-wean owHe one-s «Hooaflsm Tame-E Hmaoaamxoao-EI a was 3.0333 Tao-La ahaoaamxonu-Elb flan-319m Hem-85m TEpohxone-Ena «mow-maze Tans-3 agfishxoauemnls one s .eonpe-Hneeno hopes a-eponeoesn eoeeeeom . es.eH em.ea enmem.- m.o _\mm- memfimmao oene-ee Heated Haxonaxonoahrxe mo.eH mm.ea *oHem.H mrfl\ormmn woeamafio tone-eh assess Haseaxooeae- w me.e- fie.s- ”mah.- erp\mmum-H woe-mo-o oeatflee Heaths Harseaxoeeaer.w eases e.oHoo Q o e o e 4 R yogi-w 0% EE\ no a m sis-pom season-sou WMQHEZM Aifimmm wagwfisxmwml 9 Ema. mom szHH use; s Edema-co w Edemzo o .36 Hmlwmm -15- The tertiary amine derivatives of the mixed phenyl alkyl sulfides were obtained from the a) -chloroalky1 phenyl sulfides by treatment with a two-molar excess of the corresponding secondary amines which were piperidine, morpholine, dimethylamine, or di ethylamine, in toluene as the solvent. The reaction conditions varied widely with respect to time and temperature, depending on the nature of the secondary amine and the reactivity of the particular co-chloroalkyl phenyl sulfide us ed. The reaction periods ranged from one to nine hours and the reaction temperatures varied from 70 to 130° c. The reactions were considered complete when no more secondary amine salt formed. Rather large differences in the reactivities of the different members of the homologues series of (o-chloroalkyl phenyl sulfides was qualitatively observed. Although no attempts were made to obtain any quantitative determination of the reactivity of the chlorine atom in the a.) -chloro-‘ alkyl phenyl sulfides prepared in this work, it was found that the reactivity of the chlorine in the first three members of the homo- logous series of w-chloroalkyl phenyl sulfides was in general agree- ment with Kirner'sl8 results on such activity. Upon the completion of the reactions the free amines were iso- lated by the following method. To the reaction mixture was added water to dissolve the salt formed, followed by sodiumhydroxide until the solutions became alkaline, then the mixture was distilled with steam until the distillate gave a negative Simon's color test for a secondary amine.28 The steam distillation removed the excess secondary amine and the toluene from the reaction mixture. The remaining -15- aqueous mixture of oil was treated with hydrochloric acid to convert the oily tertiary amine into a soluble salt. Extraction with other at this point removed any unused ai-chloroalkyl phenyl sulfide. In all cases, there was no appreciable amount of unused cJ-chloroalkyl phenyl sulfide. The mixtures were then made alkaline again, whereupon an oil layer formed which was separated and later the oil was combined with the benzene extracts of the aqueous layers. After drying over anhydrous safinm sulfate,the benzene was removed on a steam bath and the remaining free amino was taken up in dry ether into which hydrogen chloride gas was passed to precipitate the amine hydrochloride. The crude andnehydrochlorides were recrystallized from.a variety of sol- vents due to their different solubility. In general isopropylalcohol, benzene, and 1,4-dioxane were found suitable for the recrystallization of the a>-piperidyl and eD-morpholylalkyl phenyl sulfide hydrochlorides, while only 1,4-dioxane was suited for'the oJ-dimethyl and ui-diethyl- aminoalkyl phenyl sulfides. In addition to the reaction conditions previously discussed, the sealed tube technique was applied for the interaction of dimethyl and diethylamine with the corresponding cn-chloroalkyl phenyl sulfides. In.the reactions involving dimethylamine 1,4-dioxane was used as a sol— vent since it was expedient to employ the amine in a 25% aqueous solution. In general, it may be said that there are a variety of influencing factors in the amination reaction. Among these factors are the re- activity of the chlorine atom in the ai-chloroalkyl phenyl sulfides and the basicity of the secondary amines. -17- The overall yields of the morpholine derivatives were in general lower then those of the piperidine derivaties, presumably because of the different basicities of the two secondary amines. Altogether, fourteen new tertiary amine derivatives of mixed phenfi;alkyl sulfides which have not previously been reported were pre- pared and some of their properties are summarized in Table V. 0f the polymethylene chlorohydrins used for the preparations of the nl—hydroxyalkyl phenyl sulfides in this investigation, ethylene chlorohydrin, trimethylene chlorohydrin and propylene chlorohydrin were readily available. Tetramethylene chlorohydrin was prepared by treating tetrahydro- furan'with gaseous hydrogenchloride according to the method employed by Starr and Hixson,22 who obtained a yield of 54-57% of the theoreti- cal: CHz-CH2 I l + HCl ————.- Ho-CH CH2 CH2 \0/ CH CH CH2°C1 2 ‘2 2 Contrary to the report of Starr and Hixson,22 who reported it required only five hours of passing hydrogen chloride gas into the reaction flask to reach a constant reaction temperature of 1050 C., it was found to take a period of thirteen hours before the reaction mixture reached a constant temperature at which point no more high boiling products were formed. The tetrahydrofuran was first heated to its boiling point (64-650 C.) on a water bath, then a slow stream of hydrogarchloride was passed -13- dampened-tam .223 a.“ usage-03.2.3 mo monsoon, mesa-5M one... moss-oases 9-5. owe-E. .._ .mm.mw 2:2 NW. 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Enos- insole-eon 2?- a a . e5 5 . mos-6m ham-"M30 esmonoww-Mwso .oodé SHE-norm 0352-39-32 Genoa-:00 amwmqtm fixqazmmm DEE mo Mumng-SHmmo “-sz MmmHm-mme > WA 93. -19.. into it. The temperature of the bath and the f10W'Of hydrogmlchloride were adjusted in a manner to maintain a constant rate of reflux. As the reaction proceeded the temperature of the reaction mixture rose, indicating an increase in the high-boiling products. The temperature of the flask was raised very slowly so as to keep the unused Iowa boiling tetrahydrofuran in contact with the hydrogenchloride. At the end of thirteen hours, the temperature remained practically constant at 90-910 c. The yield obtained from the distillation of the reaction mixture was rather low. 26% of the theoretical. The possible side re- actions which could be ascribed to the low yields have been reported.23 It was found that tetramethylene chlorohydrin reacted with hydrogen chloride in the liquid phase under pressure and at a temperature of 110° c. to give bis(4-chlorobutyl)ether. CHZ-CHZ | | HCl . CH2 CH2 + HCl -—-—+-Cl-(CH2)4OH -———r C1-(CH2)4°O°(CH2)4-Cl \\./ 0 It has also been reported that the cleavage of tetrahydrofuran to form.the corresponding dihalides could be effected with hydrogmliodide, hydrogahbromide, and hydrogenchloride.24'25 For example 1,4-dichloro- butane was readily prepared by passing a mixture of tetrahydrofuran and hydrogalchloride under pressure through a reactor maintained at 180° C., and with a proper choice of reaction concentration and re- cycling cf by-products, substantially quantitative yields of 1,4-di- chlorobutane were obtained.26 -2 O... Hzc - 3H2 HéC\ /CH2 + 2HC1 -——— Cl°(CH2)4-C1 + H 0 20 The preparation of pentamethylene chlorohydrin was accomplished by the method which Fervel and Calvary26 used for the synthesis of trimethylene chlorohydrin. This involved the interaction of the cor- responding glycol and gaseous hydrogenchloride. Ho-CHZCHZCHZCHZCHZ-OH + HCl ———-¢-HO°CH2CHZCHZCH2CH2oCl + H20 The method was based upon the quick distillation of a small quantity of the glycol by means of a rapid stream of gaseous hydrogmlchloride. Because of the higher boiling point of the product prepared here the distillation could not be carried out as rapidly as in the case of trimethylene chlorohydrin, causing difficulties in obtaining a good yield. The final yield after fractionation of the distillate was 47% of the theoretical. The product obtained was still impure and caused the IOW'yield in the preparation of the U’-hydroxyamyl phenyl sulfide. Hexamethylene chlorohydrin was prepared satisfactorily according to the method of Muller and Vanc.27 The procedure was different from thatxused in the preparation of pentamethylene chlorohydrin. It eliminated the procedure of immediate distillation of the product as it formed. This was done by replacing the downward condenser with a reflux condenser and the reaction was completed in a single operation in place of the multiple operations on small batches of the glycol as in the case of the pentamethylene glycol. -21.. HO°(CH2)6'OH .- HCl ——+ HO°(CH2)6-Cl + H20 The procedure was based upon the saturation by hydrogenchloride of the corresponding glycol at relatively low temperature over a desig- nated period of time according to Muller's data. He established the empirical relationships between the amount of glycol used, temperature of the reaction, period and rate of treatment with hydrogalchloride, yield of 1,6-dichlorohexane, 1,6-hexamethylene chlorohydrin, recovery of unreacted glycol, and the ratio of the chlorohydrin to the di- chloride. The optimum reaction conditions for obtaining a high ratio of chlorohydrin to dichloride and a low recovery of the unreacted glycol were selected on the basis of Muller'827 work. The reaction temperature actually used was 88-940 C. and the period of treatment with gaseous hydrognlchloride was three hours. Upon fractionation the crude reaction mixture a 51% yield of the pure 1,6-hexamethy1ene chlorohydrin was obtained, while Maller reported a 45.6% yield of the chlorohydrin. -22- EXPE RI MEI-HAL @-Hydroxyethyl Phenyl Sulfide In a 300 ml. three-necked round-bottom flask fitted with a stirrer, a dropping funnel, and a reflux condenser was placed 22 g. (0.2 moles) of thiophenol dissolved in 72 ml. of 10% aqueous sodium- hydroxide. To this solution.with stirring was added dropwise 20 g. (0.25 moles), of ethylene chlorohydrin over a period of a quarter hour. Immediately after the addition of the chlorohydrin was com- pleted an exthothermic reaction set in. Moderate heating was applied to the reaction flask by means of an electric mantle, whereupon a sudden cloudiness was observed in the reaction mixture. The reaction was kept at reflux for an hour to ensure completeness, in which time a clear oily layer separated. At this point heating was discontinued and.the flask and its contents were allowed to cool to room tempera- ture. The oily layer was separated by means of a separatory funnel, and the aqueous fraction was extracted twice with ether. The oil combined with the ether extract was washed twice with water and then dried over anhydrous sodhnnsulfate, followed by removal of the other on a steam bath. The oil was vacuumrdistilled using a column 30 cm. in height and 12 mm. in diameter packed with l/B" glass helices. The 37 g. of crude oil gave a feW'ml. of forerun and then a clear oil which had no unpleasant odor. The yield of the product was 24.7 g., 80.2% of the theoretical. Its physical properties were, n%0 = 1.5900, B. P. 88-970 C./l mm. Reported values are n%0 = 1.5917, B. P. 115- 116° c./2 mm.18 During the distillation about 4 g. of thiophenol were recovered from the dry-ice trap together with small amount of unreacted chlorohydrin. 523- zf -Hydroxypropyl Phenyl Sulfide Using the same apparatus as was described above, 69 g. (0.73 moles) of trimethylene chlorohydrin were added dropwise to 66 g. (0.6 moles) of thiophenol dissolved in 140 ml. of 15% aqueous sodium- hydroxide over a period of a quarter hour. The reaction mixture was then refluxed one hour with moderate heating and stirring. A clear, oily layer separated at this point and the reaction was stopped. After the separation, extraction, washing, and drying as was done in the proceeding preparation, the reaction mixture gave 120 g. of a crude oily product. This oil on fractionation gave 92 g. or 91.8% of the theoretical of the desired 1! -hydroxypropy1 phenyl sulfide which boiled at 133-135° c./l.5-3 mm. The refractive index of this material was, ngo «13 1.5793. The reported properties of this compound are ngo - 1.5813, B. P. 134-1350 c./2 mm.13 @-Hydroxypropy1 Phenyl Sulfide The same procedure and apparatus was used as in the previous preparations. To 22 g. (0.2 moles) of thiophenol dissolved in 72 ml. of 10% aqueous sodium'hydroxide were added dropwise 22 g. (0.23 moles) of propylene chlorohydrin over a period of a 15 minutes with stirring. After refluxing one hour, 40 g. of the crude product were obtained at the end of the same procedure used in the previous preparations. The crude was fractionated to give a pure product weighing 30.7 g., 91% of the theoretical, which boiled at 95-1000 C./b.5—1 mm. The refractive index of the product was, nzDO :- 1.5718. The reported values for these -24- properties are, ngo = 1.5705, B. P. 78° C./2 mm.12 A second prepara- tion of this compound gave similar results; a 91% yield, B. P. 84-101O C./3.5mm and ngo = 1.5750. 8 -Hydroxybutyl Phenyl Sulfide Using the same technique as that used in the foregoing experi- ments, the interaction of 55 g. (0.5 moles) of thiophenol dissolved in 68 m1. of 15% aqueous sodiwnhydroxide and 55.5 g. (0.51 moles) of tetramethylene chlorohydrin gave 65 g. of a crude oil in a one-hour re- action period under reflux. The fractionation of the crude product yielded 48 g., 88% of the theoretical, of the pure product which dis- tilled at 119-122°c./3-4mm. Its refractive index was, n21)O = 1.5723. Analysis for sulphur of the product gave the following results, Subs. 0.06479; BaSO4 0.04680; 8% Calc'd. 9.69; 3% Found 9.92. 6 -Hydroxyamy1 Phenyl Sulfide Following the same general procedure discussed above, the inter- action of 33 g. (0.3 moles) of thiophenol dissolved in 45 m1. of 25% aqueous sodimihydroxide‘with 57.6 g. (0.51 moles) of 1,5-pentamethylene chlorohydrin gave 60 g. of a crude oil after two hours at reflux tempera- ture. The fractionation of the crude product gave 49 g., 85.4% of the theoretical, of the pure product which boiled at 155-156°c./1-2m. The refractive index measured immediately after the distillation and before solidification was, n%0 = 1.5610. The sulfur analysis for the product was as follows: Sub. 0.12785; BaSO4 0.14975; 8% Calc'd. 16.35; 8% Found 16.09 -25- a) -Hydroxyhexyl Phenyl Sulfide By a similar procedure involving the interaction of 20 g. (0.177 moles) of thiophenol dissolved in 50 m1. of 19% aqueous sodium- hydroxide solution with 24.4 g. (0.18 moles) of 1,6-hexamethy1ene chlorohydrin there was obtained 51 g. of a crude oil in an 90-minute period at reflux temperature. Fractionation of the crude product yielded 24.7 g., 65.8% of the theoretical, of the pure product which distilled at 152-156°c./o.5mm. It was necessary in the distillation of this compound to use a shorter fractionating column, 20 cm. in height and 12 mm. diameter, and the side arm of the distilling flask was heated by a Ni-Cr electric heating element to prevent the solidi- fication of the product in the side arm during the distillation. The refractive index measured right after the distillation and before the product solidified was, n%0 = 1.5485. The sulfur analysis for this waxy compound showed the following results: Subs. 0.11860; BaSO 0.12759; 8% Calc'd. 15.26; 8% Found 14.76 4 -26- 5.55 5.55 05 05 55.0 5.5 52.0 05 52.0 5.55 5:525nresexen 5.55 55 05H 55 55.0 52 5.0 55 25.0 5.55 eseflanecseraoa 55 55 05 55 5.0 52 5.0 55 55.0 5.55 550255555555.» 25 552 05 055 0.5 05 0.5 052 50.2 022 555255055 25 5.05 05 55 5.0 5 5.0 55 55.0 55 505555055 5.25 55 05 055 5.0 55 5.0 55 55.0 55 50025nrcsaap 5.05 5.55 55 55 5.0 5 5.0 55 55.0 05 00525555 .5023 R. .m .m2. .1: moHoE 4 .m 5559.: .w memos .w 52555 sensed tees; 5052 5005550555 5555555050250 53 mom apnopooom aDHmADm 95,5555 .Hwfifigomowmla Mme mom szHflemo MQAEHM 024 wZOHeHono ZOHHodmm H> mqmdé -27- j-Chloropropyl Phenyl Sulfide To 56 g. (0.51 moles) of t—hydroxypropyl phenyl sulfide dissolved in 40.3 g. (0.51 moles) of anhydrous pyridine contained in a dry three- necked ground-glass flask fitted with reflux condenser, stirrer, and dropping; funnel was added with stirring 76 g. (0.64 moles), a 25% excess of the theoretical, of thionyl chloride. The latter reagent was added drOpwise at such a rate that no sudden temperature rise took place in the reaction mixture. The tauperature of the reaction mixture was conveniently read by dipping a long-stenmied thermometer through the condenser. The reaction was completed in a period of an hour and a half. The reaction temperature should be kept below 900 C. After cooling to room tenperature, the reaction mixture was washed with water to remove the excess thionylchloride and the pyridine hydro- chloride formed. The brownish, oily organic layer was separated by means of a separatory funnel and the aqueous layer was extracted re— peatedly with small portions of ether. The combined oil and ether extract was again.washed with water and dried over anhydrous sodium sulfate. After removal of the other the crude product weighed 93 g. Fractionation of the crude product using the column previously des- crib ed gave an oily product boiling at 102-1030C./2-3mm. The product weighed 90.8 g., 96% of the theoretical, and was slightly yellowish in color. Its refractive index was, n%0 = 1.5742. The reported value is mg? = 1.5722.18 -33- (3-Chloroethyl Phenyl Sulfide Using the above technique the interaction of 20 g. (0.15 moles) cf Q-hydroxyethyl phenyl sulfide, dissolved in 10.3 g. (0.13 moles) of pyridine, with 18 g. (0.16 moles) of thionfiichloride gave 20 g. of a crude oil in a one-hour period of reaction at a temperature of 80-1200 0. The subsequent distillation of the crude product gave 12.5 g., 55% of the theoretical, of the pure product which distilled at 99-113o c./4-6mm. The refractive index of the material was ngo = 1.5828; reported value n%P = 1.5838.18 Q -Chloropropyl Phenyl Sulfide The reaction of 148 g. (0.88 moles) of Q-hydroxypropyl phenyl sulfide, dissolved in 70 g. (0.88 moles) of anhydrous pyridine, and 130 g. (1.1 moles) of thionylchloride gave 160 g. of a crude oil in a one-hour period at a temperature ranging from 50 to 900 C., followh ing the same procedure as was used in the previous preparations. A rapid tendency toward tarring was characteristic of this reaction. Fractional distillation gave 146 g., 90% of the theoretical, of the pure product which boiled at 80-80.5°C./1mm. The refractive index of the product was, n20 = 1.5655. The reported values are, B. P. 83-860 D Co/Ool-OQZMQ, Ugo = 1.5680012 S-Chlorobutyl Phenyl Sulfide Following the same procedure as in the previous preparations, 23.7 g. (0.13 moles) of 8-hydroxybutyl phenyl sulfide dissolved in a -29- slight excess of anhydrous pyridine were treated with 18 g. (0.16 moles) of thionfiIchloride. The reaction.mixture was kept, with stir- ring, at a temperature between 50 to 80° C. for one and a half hours. The amount of crude product obtained amounted to 25.5 g. 0n distilla- tion, 16.5 g., 66% of the theoretical, of a pure product were obtained which boiled at 123°C./2mm. The refractive index of this material was, n%0 = 1.5670 and the results of analysis for sulfur were as follows: Subs. 0.09534; 8530,; 0.11352; 3% Calc'd. 15.99; 8% Found 16.35 6 -Chloroamy1 Phenyl Sulfide Using 45 g. (0.23 moles) of é-hydroxyamyl phenyl sulfide dis- solved in 18 g. (0.23 moles) of pyridine and adding 29 g. (0.25 moles) of thionyl chloride, there was obtained 35 g. of a crude oil after a two and a half hour period of reaction at a tanperature of 50 to 65° C. There was obtained by distillation 25.5 g., 71% of the theoretical, of the pure product which boiled at 127-1370C./1mm. The refractive index of this viscous product was, ngo -'-'- 1.5600 and the analysis for sulfur was as follows: Sub. 0.13151; 88.804 0.15565; 8% Calc'd. 14.95; 3% Found 16.25 (D-Chlorohexyl Phenyl Sulfide The same general procedure as previously described was employed, using 62 g. (0.32 moles) of the corresponding co-hydroxyalkyl phenyl sulfide dissolved in 25.3 g. (0.32 moles) of anhydrous pyridine and 47.2 g. (0.4 moles) of thionylchloride. This gave rise to 52 g. of a crude oil at a reaction temperature of 60-80°C. during a one-hour -30- reaction period. The fractionation of the crude product gave 44 g., 46% of the theoretical, of a pure viscous liquid which distilled at 144-1470 C./1mm. About 25 g. of a tarry residue remained after the distillation due to some decomposition. The refractive index of the product was n%0 = 1.5490 and the analysis for sulfur were as are in- di cat ed b elow: Subs. 0.13166; haso4 0.13522; 3% Calc'd. 14.03; 3% Found 14.10 -31- -33- 55 55 05-05 05 55.0 5.55 5.0 5.55 55.0 55 20855585555 25 5.55 55-05 055 55.0 52 55.0 55 55.0 55 2.25558555- 5 55 5.52 05-05 05 55.0 5.02 52.0 52 52.0 5.55 25505558555- 5 05 552 05-05 05 55.0 05 5.5 055 55.0 552 255892585555 55 5.05 05-05 05 55.0 5.05 55.0 55 25.0 55 2.25851258555- 5. 55 5. 52 052-05 05 55.0 5.02 52.0 52 52.0 05 2.255028555- 5 3500-3 V55. .5 .00 .0235 .HoE .55. .5052 .M .HoE .w 5255.2 3355555 262.85 2252525 52005 55525205 2.2555 noapooom 2503,0035 mpflopooom MmQHmAb-m 9353.55 A»&A mum“; (3-Piperidylethyl Phenyl Sulfide Hydrochloride ,CHZ-CH C6H530CH2CHz-N‘ 5 ,‘CHZ oHCl Chg-CH2 Into a dry three-necked 300 m1. ground-glass flask fitted with stirrer, reflux condenser and dropping funnel was poured a solution of 27.5 g. (0.52 moles) of piperidine dissolved in 25 m1. dried toluene. To this was added 18.5 g. (0.107 moles) of Q-chloroethyl phenyl sulfide dissolved in 25 m1. of dry toluene from a dropping funnel. The reaction mixture was stirred and allowed to proceed to completion. This was determined by the separation of sufficient piperidine hydrochloride salt, which required one and a half hours at a reflux temperature of 100° c. The initial separation of the salt started at the end of 30 minutes of reflux. After refluxing an hour and a half, there was no appreciable increase in the amount of the salt at which point the reaction.was discontinued. After cooling to room.temperature, 60 ml. of water were added to dissolve the salt formed. The reaction mixture was then made alkaline by adding a solu- tion of 4.28 g. (0.107 moles) of sodimlhydroxide dissolved in a small amount of water which caused the separation of a yellow oily layer. The mixture was smnnndistilled to remove the excess piperidine and toluene. From time to time the Simon's color test for secondary amines28 was applied to the distillate. Upon the complete removal of all the secondary amine and toluene, which required 70 minutes, the reaction mixture, while still warm, was treated with 10.4 51. of concentrated -33.. hydrochloric acid and agitated. The oily product became soluble in the acid media. The solution was then extracted with ether to remove any unreacted Q-chloroethyl phenyl sulfide. Following this 5.2 g. (0.13 moles) of sodhm hydroxide were added to obtain the free amine as an oily layer. The total volume of the mixture was then about 400 ml. The oil layer was separated and the aqueous layer was extracted with benzene until no cloudiness was visible. The combined benzene extract and oil were washed with water and dried over anhydrous sodium sulfate. Removal of the benzene was hastened by bubbling air through the solution on a steambath. The fish-odored oily free amine weighing 13 g., 50% of the theoretical, was taken up in 400 ml. of dry ether. A gentle stream of hydrogenchloride gas was passed through a small nozzle into the other solution, kept cold, until no more precipitate formed. Difficulties were frequently encountered in filtering off the sticky hydrochloride. These were best overcome by passing just enough hydrogaichloride gas for complete precipitation. The bulky hydro- '.chloride in ether was kept cold over night to help its crystallization. The salt was filtered on a Buchner funnel and the filtrate was tested with hydrognrchloride gas for complete removal of amine. The crude hydrochloride weighing 13.8 g., 50% of the theoretical, was dissolved in 100 ml. of hot, dry isopropylalcohol and decolorized twice with Norite. Overheating of the solution was avoided since the hydro- chloride was apt to decompose giving rise to a brown color in the solu- tion. Two recrystallizations from isopropfi alcohol and a final washing vdth a small amount of ether followed by drying gave 6.8 g. of a pure -34- product which crystallized in needles and melted at 185-1860 C. Analysis of the compound for nitrogen and sulfur gave the following results: N% Calc'd. 5.44; N% Found 5.55, 5.44 Subs. 0.08992; PaSO4 0.08093; 8% Calc'd. 12.45; 8% Found 12.36,12.25 0.08852 0.07895 X -Piperidylpropyl Phenyl Sulfide Hydrochloride [CHE-082 C5H53°CHZCH2CH2q - >CH2-HCl Cdg-CHZ Using the same apparatus and technique as described above 18 g. (0.1 moles) of 'I-chloropropyl phenyl sulfide dissolved in 25 ml. of toluene were added to a solution of 25.5 g. (0.3 moles) of piperidine dissolved in 15 ml. of toluene. The reaction was slower in this case and required one hour of refluxing before the piperidine hydrochloride started to separate. After similar treatment with water and alkali as in the preceding preparation, the reaction mixture was shim1distilled until it gave a negative Simon's test. This was followed by acidifica- tion, benzene extraction, and finally isolation of the free amine in an alkaline solution. After separation of the oil and extraction of the aqueous layer'with benzene followed by the removal of the benzene, the free amino was dissolved in 500 ml. of dry ether. Treatment of the other solution with hydropalchloride gas gave 30 g. of a crude salt which was decolorized and recrystallized from isopropyislcohol three times yielding 10.6 g., 39% of the theoretical, of the pure -35- crystalline compound. The product melted at 149-1500 C. and the analyses of the compound for nitrogen and sulfur gave the following results: N% Calc'd 5.16; N% Found 5.15, 5.05 Subs. 0.07259; BaSO4 0.06355; 8% Calc'd. 11.81; 8% Found 12.03 @ -Piperidylpropyl Phenyl Sulfide Hydrochloride [CHZ-CH 53 . 052 cz-i-iy ;c:d2 one 1 I CHE-CH2 CH3 CSH Following the same procedure as before, a solution of 28 g. (0.15 moles) of Q-chloropropyl phenyl sulfide in 30 ml. of toluene was added to 38.2 g. (0.45 moles) of piperidine dissolved in 50 ml. of dry toluene. The separation of piperidine hydrochloride required an hour and a half at a reflux temperature of 1000 C. The reaction was con- tinued for seven hours, after which no more salt appeared to form. After the usual treatment of the reaction mixture, there was obtained 36 g., 90% of the theoretical, of the free amine which was converted into 45 g. of the crude hydrochloride by the usual method. The product was recrystallized from.benzene four times giving 8.5 g. of the pure crystalline salt which melted 128-1290 C. The analyses of the compound for nitrogen and sulfur gave the following results: N% Calc'd. 5.16; N% Found 5.17, 5.12 Subs. 0.05613; 83304 0.04598; 3% Calc'd. 11.81; 8% Found 11.25, 11.50 0.07313 0.06122 @ -Worpholylethyl Phenyl Sulfide Hydrochloride ,CH -C‘ri CSHSS-CHZCH -§ - 4’O-HC1 Griz-Chg The procedure was the same as in the previous preparations. Using 18.5 g. (0.107 moles) of Q-chloroethyl phenyl sulfide and 26.1 g. (0.3 moles) of morpholine in 30 g. of toluene as a solvent, the salt separation failed to start after seven hours of heating at 800 C. However, morpholine hydrochloride started to separate on raising the reaction.temperature to 120° C. after one and a half hours of additional heating. There was obtained by the usual treatment of the reaction mixture 19 g. of the crude hydrochloride, 68.6% of the theoretical. The product was recrystallized from 1,4-dioxane twice giving rise to 9 g. of a pure crystalline hydrochloride salt which melted at 123- 1250 C. The analyses of the product gave the following results: N% Calc'd. 5.39; N% Found 5.38, 5.14 Subs. 0.05813; Ba804 0.05235 ; 3% Calc'd. 12.35; 3% Found 12.36, 12.04 0.05853 0.05127 ‘6 -T‘!orpholylpropy1 Phenyl Sulfide Hydrochloride fiH -CH C6H58°CHZCH2CH2-¥ . "O-HCl CdZ-Cdg By using 20.5 g. (0.11 moles) of ‘U-chloropropyl phenyl sulfide and 26.1 g. (0.3 moles) of morpholine in 20 ml. of toluene as a solvent, the morpholine hydrochloride salt separation took place after 20 minutes refluxing at 1200 C. and the reaction was completed in two and a -37- half hours. After the usual manipulations, 50 g. of the crude tertiary amine hydrochloride which corresponded to 100% of the theoreti- cal were obtained. Since most alcohols commonly available were poor solvents for the product, recrystallization was carried out by saturat- ing hot benzene with the salt and decanting the benzene solution and allowing it to cool. The material obtained from the benzene extractions was recrystallized from 1,4-dioxane. The pure crystalline material ob- tained from.three recrystallizations using 1,4-dioxane weighed 14.4 g., 44.8% of the theoretical, and melted at 142-1430 C. The analysis for nitrogen and sulfur are indicated below. N% Calc'd. 5.12; N% Found 5.10, 5.40 Subs. 0.08127; Ba304 0.06783; 8% Calc'd. 11.72; 8% Found 11.47, 11.58 0.07859 0.06626 Q -mbrpholylpropyl Phenyl Sulfide Hydrochloride CH3 [CHz-CH H S-CH tn - N ‘O-HCl 5 2 \ -I CHz-CHZ Ce Interaction of 32.45 g. (0.174 moles) of @c-chloropropyl phenyl sulfide and 40 g. (0.45 moles) of morpholine dissolved in 30 g. of toluene gave morpholine hydrochloride salt separation after a period of five hours refluxing at 1250 C. and the reaction was completed with an additional seven hours at the same temperature. After the usual treatment of the reaction mixture, 24 g., 55% of the theoretical, of the crude hydrochloride were obtained. On two recrystallizations from 1,4-dioxane, 9.9 g., 20.8% of the theoretical, of a pure crystalline -38.. salt with a melting point of 146-1480 C. was obtained. The analyses for nitrogen and sulfur of the compound gave the following results: N% Calc'd. 5.12; '% Found 5.07, 5.18 Subs. 0.08787; Baso4 0.07255; 3% Calc'd. 11.72; 8% Found 11.55, 11.54 0.08590 0.07086 8 -Piperidylbutyl Phenyl Sulfide Hydrochloride [CH2 -CHZ CSHSS-CHZCHZCHZCHz-Q , ;CH2°H01 Cliz -CH2 Employing 14 g. (0.07 moles) of 8 -chlor0butyl phenyl sulfide, 18 g. (0.21 moles) of piperidine, and 20 nd. of toluene as a solvent, produced the first piperidine hydrochloride salt separation after ten minutes of reaction at 800 C. The total period required for the com- pletion of the reaction was only one hour at the same temperature. The hydrochloride obtained through the usual procedure was dissolved directly in 1,4-dioxane and on further recrystallizations gave 6.7 g., 34% of the theoretical, of the pure crystalline product which melted at 137-1380 C. The analyses for nitrogen and sulfur in the compound gave the following data; N% Calc'd. 4.90; N% Found 4.97, 4.83 Subs. 0.08891; Baso4 0.07159; 5% Calc'd. 11.25; 3% Found 11.05, 11.05 0.07259 0.05848 -39- 8 -”orpholylbutyl Phenyl Sulfide Hydrochloride 05 -Cd ’J 2 U- a c H SoCH CH CH CH -N 2 2 2 6 5 2 ‘CHz-cng 0°HC1 Reacting together 18 g. (0.09 moles) of 8 -chlorobuty1 phenyl sulfide and 23.5 g. (0.27 moles) of morpholine in 20 m1. of toluene as a solvent caused an initial salt separation after an hour and a quarter at a reaction temperature of 78° C. The reaction.was completed after an additional twenty-four period at the same temperature. By the usual proCedures, 10 g., 38.7% of the theoretical, of a crude hydro- chloride were Obtained. Three recrystallizations of the product from 1,4-dioxane yielded 3.7 g. of the pure, crystalline product which melted at 113-1140 0. The analyses for nitrogen and sulfur for the compound gave the following data. N% Calc'd. 4.87; N% Found 4.83; 5.00 Subs. 0.05783; BaSO4 0.04676; 8% Calc'd. 11.15; 8% Found 11.10, 11.05 0.06815 0.05483 5 -Piperidylamy1 Phenyl Sulfide Hydrochloride pHZ-CH CSHSS'CHZCHZCHZCHZCHzeq -;CH2°hCl CHz-Chz From the reaction of'8 g. (0.037 moles) of £'-chloroamyl phenyl sulfide and 8.6 g. (0.111 moles) of piperidine in 15 ml. of toluene as a solvent there resulted a poor yield of the corresponding tertiary amine at a reaction temperature of 700 C. The time required to the initial separation of piperidine hydrochloride was one hour and required an additional hour and a half for completion of the reaction. The crude hydrochloride obtained by the subsequent treatment was re- crystallized twice from 1,4-dioxane, giving rise to 1.0 g., 88% of the theoretical, of the final product which melted at 118-122° C. Analytical data are as follows: N% Calc'd. 4.67; N% Found 5.24, 5.33 Subs. 0.02407; BaSO4 0.01768; 8% Calc'd. 10.70; 3% Found 10.10 6 -Morpholylamyl Phenyl Sulfide Hydrochloride [CH2 -CH2 CHz-CHZ CGHS Treatment of 8 g. (0.037 moles) of 6-chloroamy1 phenyl sulfide with 8.8 g. (0.111 moles) of morpholine in 15 ml. of toluene as a solvent produced initial separation of morpholine hydrochloride salt after one hour of reaction, and the reaction.was completed in an addi- tional half hour. A yield of 2.1 g., 15.2% of the theoretical, of the pure hydrochloride was obtained after seVeral crystallizations from 1,4-dioxane. It melted at 117-1190 C. and analyzed to give the fOIIOWb ing results: N% Calc'd. 4.64; N% Found 4.67, 4.77 Subs. 0.06103; Ba304 0.04758; 8% Calc'd. 10.63; 8% Found 10.70, 10.67 0.03277 0.02545 -41- u)-Piperidylhexy1 Phenyl Sulfide Hydrochloride [CHZ-CH C6H5SoCHchZCHchzCH20fl2-¥ _/CH2.HC1 CH -Cd 2 2 From 18 g. (0.079 moles) of d>~chlorohexyl phenyl sulfide, 20.2 g. (0.24 moles) of piperidine, and 10 ml. of toluene at a reaction temperature of 100° C. there was obtained the initial salt separation in two and a half hours and the reaction was completed in an hour of additional heating. The 15 g., 57% of the theoretical, of crude hydro- chloride gave 8.25 g. of pure crystalline salt after several recrystal- lizations from 1,4-dioxane. The product had a melting point of 119-1210 C. and'was analyzed to give the following results: NU. Calc'd. 4.47; 1137. Found 4.66, 4.66 Subs. 0.06980; BaSO4 0.04993; 3% Calc'd. 10.22; 8% Found 9.83, 9.96 0.07534 0.05463 (0 -Morpholy1hexyl Phenyl Sulfide Hydrochloride (CHZ-CHZ CGHSS°CH2CH2CHZCH2CH2CH2-q ;0°HCI CH ~CH 2 2 Interaction of 24 g. (0.11 moles) of q)-chlorohexyl phenyl sulfide and 28 g. (0.33 moles) of morpholine in 15 ml. of toluene as a solvent gave the first salt separation in three and a half hours of reaction at 110° C. The reaction was completed in an additional three hours. The 23 g. of crude hydrochloride, after a few recrystallizations from 1,4-dioxane, gave 15.6 g., 41% of the theoretical, of a white, waxy material which melted at 112-1240 C. The analyses of this compound showed the following results. N% Calc'd. 4.44; 119: Found 4.51, 4.52 Subs. 0.05055; Baso4 0.04251; 8%‘Ca1c'd. 10.15; S% Found 9.71, 9.83 0.08012 0.05734 3 -Diethylaminopropy1 Phenyl Sulfide Iydrochloride 06555.052052052-N(0255)2o501 The reaction was carried out in a heavy walled Pyrex sealed tube heated in an electric oven. A solution of 25 g. (0.134 moles) of U -chloropropyl phenyl sulfide and 18 g. (0.253 moles) of dimethylamine in 20 m1. of toluene as a solvent was placed in the tube, after which it was sealed. Heating was slowly applied over a period of 22 hours reaching a final temperature of 130° C. The tube was allowed to 0001 over night without removing it from.the oven. Procedure thereafter was identical to those used in the preceding preparations. The 25 g., 81% of the theoretical, of the free amine gave 25 g. of crude hydrochloride, which by subsequent crystallizations from.l,4-dioxane yielded 1.35 g. of a pure compound. The product melted at 131-1320 C. The analyses of the product resulted in the following data: N% Calc'd. 5.46; N% Found 6.13, 6.26 Subs. 0.05076; Ba804 0.04731; 8% Calc'd. 12.36; 8% Found 12.80, 13.07 0.05514 0.05246 -43... @ -Dimethylaminoethy1 Phenyl Sulfide Hydrochloride C6H5S~CHZCH2N°(CH3)2°HC1 Using the same sealed-tube method, 16 g. (0.1 moles) of (8-chloro- ethyl phenyl sulfide, 52 g. of a 25% aqueous solution of dimethylamine (equivalent to 13 g. or 0.29 moles), and 135 ml. of 1,4-dioxane as a solvent, there was obtained 7 g. of a pure hydrochloride after a 15 hour reaction period at 140-1500 C. By similar manipulations as were applied in the previous preparations, a yield corresponding to 40% of the theoretical was obtained. The hydrochloride salt thus obtained melted at 114-1150 0. The analyses for nitrogen and sulfur for the compound gave the following results: N% Calc'd. 6.44; N% Found 6.26, 6.55 Subs. 0.11102; Ba804 0.11918; 8% Calc'd 14.74; 8% Found 14.74, 14.88 0.08396 0.09099 -44.. ocounom o .opexoflvie.fi a $3630 HhmoamomH e 0000c 0 00 0.00 0.00 1... 00-000 000 $0.00 0.00 80.00 0.00 55515050.. 0 .c.o Hzmoam n .i 1. 0.00 ...i 000 00 00.00 0.00 $0.00 0.00 105500530- 0 0 00 0.00 0.0 0.0 0: 00 30.3 0.00 20.00 0.00 185000005073 0 u- .i 0.0 0.0 000 00 “00.00 0.00 20.8 0.00 005000350083 0 I. ..- 0.0 0.0 00 00 20.00 0.0 00.00 0.0 15102050.. 0 0 .i i 04 0.0 00 00 20.00 0.0 00.00 0.0 0051005000- 0 0 00 0.00 0.00 0.0 00. 00 £0.00 0.00 $0.00 0.00 00500000005010 0 00 0.00 0.0 0.0 00 00 20.00 0.00 20.00 0.00 0331020000- w 0 00 0.00 0.00 0.0 000 00 00.00 0.00 £0.00 0.00 00080000000000- 0 o 000 0.00 0.0 0.0 02-000 00 0.0.00 0.00 “00.00 0.00 00080100503- 0 o . e 000 0.00 0.0 0.0 000 00 00.00 0.00 20.3 0.00 108010000507 0 s 02 0.00 .1. 0.0 .3. 00 00.00 0.00 00.3 0.00 1023035000.. 0 0 00 0.00 0.0 0.0 000 00 00.00 0.00 2.0.8 0.0 10500020030- 0 a 00 0.00 0.0 0.0 000 00 00.00 0.0.0 20.00 0.00 0005100503.. 0 ppm» X .m .0: .0: .oo .HE AmoHoEv mm AmoHoEV .0 ooflaofinoonemm Ifiom ovfiaoanooaoam nowaom .Ehom pesos ecoSHoe onwfi< .oom ozdxfleoaoflno ovwmfism ammonmi .pmauo eeopo mo .xm vfiom .Nm apnevoeom ”menSoQEoo 00o00 eeo00000o0 soepoeoa iii.“ meHmoqmoomowm mmHmAbm waumdwzmmm QmNHE mo wm>HH<5Hme msz< ~m mqm-hydroxyalkyl phenyl sulfide was dissolved in 3 m1. of dry pyridine and treated with one gram of the corresponding benzoyl chloride. After the initial reaction had subsided, the mixture was heated gently with shaking until a clear solution resulted. It was then poured into 10 ml. of water with stirring. This caused an oil to separate and on cooling the oil solidified. The solid was recrystallized from a suit- able solvent. ABIALYS § Determination of Nitrogen - The procedure applied in this work was that of Clark31 which employed the Kjeldahl method on a semimicro scale. Using a ground- glass micro-Kjeldahl distilling apparatus, a mixture of 40-100 mg. of sample, 0.1 g. of a mixture of mercuric oxide and potassium.sulfate in a ratio of 8 to 100, and 3 ml. of concentrated sulfuric acid was di- gested over a six-hour period. After cooling the digestion mixture, it was diluted with 10 ml. of water and.Shmnldistilled after adding 10-12 ml. (40%) aqueous mxfium hydroxide solution. The receiver con- tained 6 m1. of 4% boric acid and two drops of a 0.1% ethanolic solu- tion of methyl red with about a one-half drop of methylene blue as an indicator. The distillation was continued until 50 rd. of distillate had been collected. The receiving flask was then lowered until the lower tip of the condenser was just above the content of the receiver and the distillation was continued until 2-3 ml. more of distillate had collected so as to wash off the inner surface of the condensing tube. The rate of distillation must be adjusted so that no mechanical carry- ing over of the distilling mixture into the receiver occurs. The temperature of the receiver must be kept below400 C. The ammonia received in the boric acid solution was titrated with a standard hydro- chloric acid solution using a microburet. The end point was easily determined by comparison with a reference solution. A blank due to reagents must also be determined and subtracted from the buret reading. -49'. Determination of Sulfur A semimicro determination of sulphur was carried out gravimetric- ally using the Parr bomb fusion method of Lincoln, Carney, and"7'1"a_gner.'32 The organic sulfur compound in an amount corresponding to 20-100 mg. of barium sulfate was fused with a mixture of 0.2 g. of powdered potas- sium perchlorate, 0.15 g. of sucrose, and 4 g. of granular sodium peroxide. The sulfur was determined as barium sulfate. _50- SIE‘IIIA RY The three:» -hydroxyalkyl phenyl sulfides with four, five, and six carbon atoms in the alkyl chain were prepared for the first time and some of their properties were determined. The 3,5-dinitrohenzoate derivatives of the a)-hydroxyalkyl phenyl sulfides with two, three, four, five and six carbon in the alkyl chain were prepared for the first time and some of their properties were determined. In addition the p-nitrobenzoates of the above 41—hydroxyalkyl phenyl sulfides with the exception. G-hydroxypropyl phenyl sulfide were also prepared as new compound and some of their properties were determined. The following co-haloalkyl phenyl sulfides were prepared as new compounds and some of their properties were determined: ,s-chloro— butyl; e-chloroamyl, and u)-chlorohexyl. Fourteen tertiary amine derivatives of mixed phenylalkyl sulfide hydrochlorides were synthesized for the first time and some of their properties were investigated. -51- BI BLIOGRAPHY P.) {\3 Einhorn and 5. T’Eilfelder, Ann. 371, 131 (1909). I—I. PerQa-n, LT. Chem. 300., 9:5, 1‘793, (19'38). Erdtman and F. Léfgren, Svensk Fem. Tid. 4d, 163 (1937), C. A., 31, 7FS4UQ L. BuchEl and B. Tohauber, Compt. rend. soc. biol., 41, 34-5, (1947). Fohler, Compt. rend. soc. bi01., 141, 255-4, (1947). (1 0. Vhrvel and A. L. Tanenbaum, "Crganic Syntheses," Col. V—I, John iiley and Sons, 100., lew'York, E. Y., 1944, p. 435. 1. Clams and Perkin, J. Chem. 5oc., 1312 542, (1922). Steinkopf, J. Herold and J. St6hr, Ber., 53, 1012, (1920). Lecher and P. aoochlin, Ber.,.58, 414, (1925). 0. Yenitzesen and F. Scarlatescu, 85r.,.9:§, 589, (1535). l. Loyd and a. 2. ”arli, 9er., 1992 2117-55, (1914). c. Fuson and J. H. Foehneke, J. Org. Chen., 132 705, (1949). Adams, ”Crganic deactions," John Kiley and Sons, Inc., Yew York, U. 2., 1944, 7-11, p. 178: -- i n. Renshow and D. E. Searle, J. Am, Chem. 800., 50, 2057, (1937). Cilman, T..A. Plunkett, L. Tolman, L. Fullhart, and H. S. Broadbent, J..nm. Chem. 800., 67, 1842-5, (1945). Gilman and L. a. Joods, J. Am. Chem. Soc., 62, 1844, (1945). ". dennet and 7. A. Berry, J. Chen. 900.,‘130, 1676, (1927). 9. Kirner and 0. n. Richter, J..Am. Chem. 800., g}, 5409, (1929). 0. Powell, J. Am. Chem. Soc., 35, 2709, (1925). Tarzens, Compt. rend., 152) 1314, (1911); C. A., 5, 3410, (1911). Foelle, 8er., 19: 1955, (1880). Starr and R. Y. dixon, "Crganic Syntheses," Col. ”-11, John niley and Sons, Inc., 1Tew York, F. Y., 1944, p. 571. ’1 he ‘3. Pftarit, 2,245,509. Fried and n. 0. Fleene, J. Am. Chem. 300., E2, 325? (1940); C. A., 35, 73. Fried and i. 0.A1ileene, J. Am. Chen. 300., 63, 2691, (1:41); f‘\ C. ’45., 36’ 4; S. Fervel and H. 0. Calverv, "Crganic Syntheses," Col. V-I, D John Jiley and Sons, Inc., Few York, T. Y., 1944, o. 533. ller ans E. Vane, ”onatshefte ffir Chemie, 77, 259-63, (1947). P. fhlliken, "A Tethod for the Identification of Pure Organic Comoounds," John Kiley and Sons, Inc., Few York, F. Y., 1916, ’if-ll, p. 430 7. ”CElvain and f. P. Carney, J. Am. Chem. 800., 68, 2596, (1946). hril ier 511d 0. Fuson, "The Systematic Identification of manic Compounds," John Ailey and Eons, Inc., Yew York, F. Y., 49, p. 165 P. Clark, "Semimicro Qu ant its tive Organic Analysis, .. . Acadedic Press, Inc., 19 43, p. 37. 9, Lincoln, 9. S. Carney and C. manner, Ind. 304. Chem., Anal. 35., 15, 555—5 1, (1941). VITA NAME: No on Hwi Kim BORN: August 29, 1919,in Taeku, Korea. ACADEMIC CAREER: April 1938 - March 1941 April 1941 — September 1943 ”arch 1949 - February 1951 DEGREES HELD: Master of Science -— 1943 -- Fukuoka Junior College, Fukuoka , Japan Kyoto Imperial University, Department of Industrial Chemistry, Kyoto, Japan Michigan State College, Department of Chemistry, East Lansing, Michigan Kyoto Imperial University Kyoto, Japan 4;. ”1'11! w W" ‘ K49 Kim 255914 11111111111111111111\11111111111 _ 31293 02446 7601 .